N-alkenyltetracycline derivatives

ABSTRACT

Novel N-alkenyltetracycline derivatives, for example, N-(1methyl-2(2-thionyl)-1-butenyl)tetracycline represented by the formula   The compounds have excellent antibacterial action as compared with tetracycline.

United States Patent 1 Murakami et al.

[ N-ALKENYLTETRACYCLINE DERIVATIVES [75] inventors: Masuo Murakami, Tokyo; Masaru lwanami, Yokohama; Tadao Shibanuma, Asaka; Masaharu F ujimoto, Tokyo; Norio Sato;

Ryutaro Kawai, both of Saitama;

Kuniichiro Yano, Tokorozawa, all of Japan Yamanouchi Pharmaceutical Co.,

Ltd., Tokyo, Japan [22] Filed: Nov. 14, 1973 [21] App]. No.: 415,832

Related US. Application Data [62] Division of Ser. No. 205,4l4, Dec. 6, I971, Pat. No.

[73] Assignee:

[30] Foreign Application Priority Data Dec. 9, 1970 Japan 45-109160 Dec. 26, 1970 Japan 45-128347 [52] US. Cl.. 260/332.2 R; 260/327 TH; 260/3292 July 15, 1975 [51] Int. Cl C07d 63/00 [58] Field of Search 260/3322 R, 559 AT, 329.2, 260/327 TH Primary Examiner-Bernard Helfin Assistant ExaminerA. Siegel Attorney, Agent, or Firm-Burgess, Ryan & Wayne [57] ABSTRACT Novel N-alkenyltetracycline derivatives, for example, N-[ l-methyl-2( 2-thionyl)-l-butenyl]tetracycline represented by the formula The compounds have excellent antibacterial action as compared with tetracycline.

7 Claims, No Drawings 1 N-ALKENYLTETRACYCLINE DERIVATIVES This is a division of application Ser. No. 205,414, filed Dec. 6, 1971 now US. Pat. No. 3,808,274.

DETAILED EXPLANATION OF THE INVENTION The present invention relates to a N-alkenyltetracycline derivatives having excellent antibacterial action. More particularly, the invention relates to N-alkyenyltetracycline derivative represented by the formula III wherein R represents a hydrogen atom, a halogen atom, or a dimethylamino group; R represents a hydrogen atom or a methyl group; R represents a hydrogen atom or a hydroxyl group; said R and R when combined with each other form a methylene group, R represents a hydrogen atom or a hydroxyl group; and R R and R which may be the same or different, each represent a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a mercapto group, a carboxyl group, a carbamoyl group, an alkoxyl group such as methoxy and ethoxy, an aryloxy group such as phenoxy, an alkylthio group such as ethylthio, an arylthio group such as phenylthio, an alkoxycarbonyl group such as ethoxycarbonyl and tbutoxycarbonyl, an aryloxycarbonyl group such as phenoxycarbonyl, an alkylsulfonyl group such as methylsulfonyl and allylsulfonyl, an arylsulfonyl group such as phenylsulfonyl, an alkanoyl group such as acetyl and t-butyryl, an aroyl group such as benzoyl, an alkylcarbamoyl group such as ethylcarbamoyl, an arylcarbamoyl group such as phenylcarbamoyl, an alkyl group such as a saturated alkyl group, e.g., methyl, ethyl, propyl, isopropyl, isobutyl, t-butyl, amyl, and actyl and an unsaturated alkyl group, e.g., 2-propionyl and allyl, a cycloalkyl group such as a saturated cycloalkyl group, e.g., cyclohexyl, cycloheptyl, etc., and an unsaturated cycloalkyl group, e.g., cyclohexenyl and indenyl, an aryl group such as phenyl and naphthyl, an aralkyl group such as benzyl, phenethyl, and 2-phenylisobutyl, and a heterocyclic ring group such as pyridyl, pyrimidyl, thienyl, pyranyl, pyrazolyl, furyl, thiazolyl, and chromanyl.

Two groups of the members R R and R may combine to form an alkylene group such as a saturated alkylene group, e.g., trimethylene, tetramethylene, pentamethylene, etc.; an unsaturated alkylene group, e.g., butenylen, etc.; a heteroatom-containing saturated alkylene group, eg, Z-azatetramethylene (CH N- I-ICH CH Z-thiatrimethylene (CH- S--CH 2-oxatetramethylene (CH OCH- CH l-aza-3-oxatetramethylene (NH-CH- OCH etc., a heteroatom-containing unsaturated alkylene group, e.g., l-oXa-2-butenylene boxyl group, a sulfone group, a methoxy group, a butoxyl group, a methylthio group, a phenoxy group, a phenylthio group, a methoxycarbonyl group, an ethoxycarbonyl group, a phenoxycarbonyl group, a methylsulfonyl group, a phenylsulfonyl group, a ptoluenesulfonyl group, an acetyl group, a benzoyl group, a furyl group, or a thienyl group and further other groups exceptalkyl, cycloalkyl, and alkylene shown by the groups R;,, R and R may have the above substituent or a methyl group, an ethyl group, a butyl group, an isobutyl group, a t-butyl group, an ally] group, a cyclohexyl group, a tetramethylene group, a butadienylene (CH=CHCH=CH-), a 3-ethylbutadienylene Jaws-8 b?- etc.

The compounds of this invention represented by'the formula III are compounds that have never been reported in any references and are valuable antibiotics having excellent antibacterial power which are effective not only against grampositive and gramnegative bacteria but also to tetracycline resisting bacteria.

The compounds of this invention represented by the formula III are prepared by the reaction of the tetracycline represented by the formula I wherein R R R and R have the same significance as in the formula III with the enamine compound represented by the formula II n Iii: 0, 6

wherein R R and R have the same significance as in the formula III and R and R which may be same or different, each represents an alkyl group such as methyl, ethyl, propyl, isobutyl and t-butyl or an aryl group such as phenyl, said R and R may combine with a nitrogen atom to form a heterocyclic ring, which may contain a heteroatom, such as a piperidine ring, a pyrrolidine ring, a morpholine ring, or a quinoline ring It is not known that the enamine compound having an acid amide structure as the compound of the formula III is obtained by the reaction of the compound having a carbamoyl structure as the compound of the formula I with the enamine type compound as the compound of formula II, that is, such a reaction is a novel reaction discovered first by the inventors.

Examples of the tetracyclines represented by the (O-CH==CI-I-CH etc. Furthermore, each of thbove formula I, which is used as a starting material in groups R R and R may have, as a substituent, a halogen atom, a nitro group, a cyano group, an amino group, a dimethylamino group, an imino group, a hydroxyl group, a mercapto group, a formyl group, a carthe aforesaid reaction includes, e.g., tetracycline, 5-oxytetracycline, 7-chlorotetracycline, 7- bromotetracycline, 5-oxy-7-chlorotetracycline, 6-deoxy-5-oxytetracycline, 6-dioxytetracycline, 6-

3 4 deoxy-6-demethyltetracyclme, 6-demethyltetracycl1ne, Table LCOntinued 6-demethyl-7-chlorotetracycl1ne,. 6- methylenetetracycline, 6-methylene-5 oxytetracycllne, Compounds Orgw Concentration of Sample (meg/ml) -oxy-6-demethyltetracycline, and 7- d1methylammo-6- "isms 5 6 5 1,50 039 9 demethyl-6-deoxytetracycline. 5 18 B Among theenamme compounds shown by the for- A mula II, there may be included novel compounds and 20 g I I I I 1' they may be prepared by the reaction of corresponding 27 B ketones and amines (see; ENAMINES" written by A. '3 I I 1 Gilbert Cook, published by Marcel Dekker Col in A 1969). V I, 29 B The reaction of preparing the compounds of this in- 36 '3 I I I I I vention IS conducted by reacting the tetracycline of the A formula I and an equimolar to excessive molar amount, 38 R I I I I i preferably about twice by mol that of the enamine com- 42 B pound of the formula II in an organic solvent such as 43 I I dimethyl formamide, and the like. The reaction is con- A I I I ducted at room temperature or under cooling or heat- H 44 B ing but is ordinarily conducted at room temperature in 45 g I I I I I the presence of a mineral acid such as hydrochloric A acid, hydrobromic acid, etc., with stirring for few 5O 2 I I I I 1 hours. In this case, however, a mineral acid salt of the 5 B tetracycline I and/or a mineral acid (immonium salt) of A h d u b d 1' f h 56 B I I t e enamine compoun may e use in p ace 0 t e A mineral acid. H 3 B I I The desired compounds III of this invention thus pre- 69 g I I I I I pared may be isolated from the reaction product liquid A by an ordinary chemical operation such as extraction, 70 R I I I i 1 etc., and if necessary, the product may be further puri- 73 B fied by reprecipitation, recrystallization and the like. 75

In the following experiments, the antibacterial ac- 1, A I I i tions of the compounds of this invention to a standard H I 78 B strain and a tetracycline resisting bacterium were com- 83 g I I I I I pared with those of tetracycline. A

85 B EXPERIMENT I 1 A 86 B An ordinary agar culture medium (pl-I 7) containing A 25, 6.25, 1.56, 0.39 010.9 meg/ml of the test sample 87 2 I I I 1 i was inoculated (A) a standard strain, Staphylococcus 88 B aureus FDA 209p or (B) a tetracycline resisting bacte- 4O 89 Q I I I I I ria, Staphylococcus aureus Onuma by an agar dilution A I method and when the bacterium'was cultivated for 24 90 2 I hours at 37C, it was observed whether the bacterium 91 B I grew or not. The case where the growth of the bacte- A rium was observed was denoted by and the case H 93 K I I I I where the growth was not observed was denoted by 94 B the results being shown in Table I. 98 I I I i 1 As clear from Table I, the compounds of this inven- A 1 tion have excellent antibacterial activity with respect to H 104 R the tetracycline resisting bacterrium. I '05 B i I In the following experiment, the antibacterial spectra A of the compounds of this invention were compared H K I I I I I with those of tetracycline. 109 B Table I 113 B Compounds Orga- Concentration of Sample (meg/ml) I A I nisms 25 6.25 1.50 0.39 0.09 1 [9 B Tetracycline B A Product of A 127 B Example 2 B A A 128 B 6 B A A 129 B 14 B A A 130 B 16 B A A 131 B 17 B A Table l-Continued the reaction was over, the solvent was distilled away from the reaction product liquid and water was added Cumpqnnds Q 5 Concentration of Sample g/ to the residue to form a precipitate, which was recovfi Isms ered by filtration. The precipitate thus recovered was 13 g I i dissolved in 20 ml of chloroform, the solution was .1 A washed with water, 2% aqueous acetic acid solution, I 135 R I I t t and then water, and after drying the solution over anhy- 136 B drous sodium sulfate, chloroform was distilled away. 1 A Petroleum ether was added to the residue and the 137 B n A crystalline powder of N-(l,2-dimethyl-l-propenyl)tet- H 138 B racycline thus precipitated was recovered by filtration.

A The am 1 r m d 0 [39 B oun o epro uct was .Sg. A Elemental analysls as C I-1 N 0 141 B 1, A C H N 142 B Calculated: 63.27 6.29 5.47 I: A Found: 63.36 6.29 5.46

143 B H A 144 B EXAMPLE 2 In 10 ml of dimethylformamide was dissolved 1.0 of g EXPERIMENT tetracycllne hydrochloride and after adding to the solu- To a heart infusion agar culture medium containing iOH 0.895g 0f l-phenyl-Z-piperidinO-l-b the 100, 50, 25, 12,5, 6,25, 3,13 or 1,56 1 f th t mixture was stirred for 4 hours at room temperature. sample was inoculated (A)) Staphylococcus a eu After the reaction was over, the solvent was distilled FDA 209p, (B) SlaphylOCOCCuy-,aureuS O (C) away from the reaction product liquid and after adding Staphylococcus aureus $hi i hi,(1)) E, 1 (E) P water to the residue, the product was extracted with teus vulgaris, (F) Pseudomonas aeroginosa, (G) Salmo- ChlOtOfOfmnella typhi H901W, or (H) Shigella sonnei 11 37148 d The is clear was distilled away, ether and petroleum then the bacerium was cultivated for 24 hours at 37C ether were added to the residue, and the precipitate It was observed whether th ba t rium grew o not, thus formed was bacterium. by filtration. The precipi- The case where the growth of the bacterium was btate was dissolved in chloroform, the solution was then served was denoted by and the case where the washed with a 2% aqueous acetic acid solution and growth was not observed was denoted by the rethen with water, and chloroform was distilled away. s ns bei sh i T bl [I When an ether-petroleum ether solvent was added to As clear from the above results shown in the Table the residue followed by purification, about 1.0g of N- I], the compounds of this invention had broad antibac- (l-ethyl-2-phenylethenyl)tetracycline was obtained. terial spectra. However, the product contained a small amount of a Compounds Orga- Concentration of Sample (meg/ml) nisms 100 25 12.5 6.25 3.13 L56 A B v C Tetracycline D E -1- F o 11 A B c product of D Example 17 E F G H A B C D Product of Example l23 E F G 1-1 The invention will now be illustrated in and by the hydrogen following examples.

EXAMPLE 1 rearrangement product, N-(l-benzyl-lpropyl)tetracycline.

Elemental analysis as C H N O C H N Calculated: 66.89 5.96 4.87

Found: 66.53 5.92 4.89

EXAMPLE 3 In 5.5 ml of dimethylformamide was dissolved 0.8g of tetracycline hydrochloride and after adding to the solution 0.7g of l-( 4-met hylthiazole-2-yl )-2- piperidinopropene, the mixture was heated to 70C for 3 hours. After the reaction was over, the solvent was distilled away under a reduced pressure and after adding to the residue ml of water, the product was extracted with chloroform. After washing the extract with 2% aqueous acetic acid solution and then 2% aqueous sodium bicarbonate solution, the solution was distilled away and then ml of ether was added to the residue to form a precipitate, which was recovered by filtration to provide 0.8g of a yellow powder of N-[ l-methyl-Z- (4-methylthiazole-2-yl)ethenyl1tetracycline having a melting point of 150 157C (decomposed).

Elemental analysis as C I-I N O SH O:

Calculated: 58.09 5.55 7.01 5.35

Found: 57.74 5.28 6.75 5.24

EXAMPLE 4 In 5 ml of dimethylformamide was dissolved 0.7g of tetracycline hydrochloride and after adding to the solution 0.7g of l-(2,4-dimethylpyrimidine-6-yl)-2- piperidinopropene, the mixture was heated to 70C for 4 hours. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and after adding to the residue 5 ml of water, the product was extracted .by chloroform. After washing the extractwith 2% aqueous acetic acid solution and then 2% aqueous sodium bicarbonate solution, the solvent was distilled away and then 10 ml of ether was addedto the residue to form a precipitate, which was recovered by filtration to provide 0.3g of N- [l-methyl- 2-(2,4-dimethylpyrimidine-6-yl)ethenyl]tetracycline having a melting point of l54l62C (decomposed).

Elementary analysis as C H N O H O:

C (70) H N Calculated: 61.17 5.97 9.21 Found: 61.08 5.70 9.13

EXAMPLE 5 chloroform. The extract was washed with water, 2%

aqueous acetic acid solution, 2% aqueous sodium bicarbonate solution, and then water, and after drying over anhydrous magnesium sulfate, the solvent was distilled away under a reduced pressure and ether and pethe mixture was stirred for 14 hours at room temperature. After the reaction was over, the solventwas distilled away under a reduced pressure and after adding water to the residue, the product was extracted with chloroform. The extract was washed with water, 2% aqueous acetic acid solution, 2% aqueous sodium bicarbonate solution, and then water and after drying over anhydrous magnesium sulfate, the solvent was distilled away under a reduced pressure. Ether and petroleum ether were added to the residue and the precipitate thus formed was recovered by filtration to provide 0.8g of N-[2-(p-nitrophenyl)-l-methylethenyl]- tetracyclin.

Elemental analysis as C H N O C (70 H (7 N Calculated: 61.48 5.16 6.94 Found: 61.23 5.28 6.72

EXAMPLE 7 (xii-2%) 74.2 (1 H) (CDCl g i Elemental analysis as c H.,,N o,.H o;

C (70) H Calculated: 62.62 7.06 685 Found: 62.50 g 6.77 6.56

EXAMPLE 8 In 10 ml of dimethylformamide was dissolved-1 .0g. of tetracycline hydrochloride and after adding to the solution 0.7 g of N-cyclohexenylpyrolidine, the mixture was stirred for 5 hours at room temperature. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and when water was added'to the residue thus obtained and the pH of the solution was adjusted to 5 with l N hydrochloric acid, a precipitate was formed. The precipitate Y recovered by filtration was washed with water, and distroleum ether were added to the residue, thereafter the precipitate thus formed was recovered by filtration to provide 0.5g of N-( 1-methyl-l-decenyl)-tetracycline.

Elemental analysis as C I-I N O I In 7 ml of dimethylformamide was dissolved 1.0g of tetracycline hydrochloride and after adding to the solution 1.1g of l-p-nitrophenyl-2-morpholino-l-propene,

solved in chloroform, and reprecipitated from chloroform-ether to provide 0.3g of N-cyclohexenyltetracycline.

EXAMPLE 9 In 10 ml of dimethylformamide was dissolved 1.0g of tetracycline hydrochloride and after adding 0.7g of N- 4-methylcyclohexenylpiperidine to the solution, the mixture was stirred for 5 hours at room temperature. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and when water was added to theresidue thus obtained, a precipitate was formed. The. precipitate was recovered by filtration and washed" with water to provide 0.7g of N-4-methylcyclohexenyltetracycline piperidine salt. Y I

Nuclear magnetic resonance: alkene hydrogen r 3.9 (1H) (CD C1 Elemental analysis as C l-1 N O .l-1 O:

Calculated: 63.63 7.38 6.55

Found: 63.90 7.21 6.30

EXAMPLE 1O 2 s (R-C-lI 1- 3.88 (1H) (CD C1 Elemental analysis as CggHgnNgOgCl:

C (7:) H (7:) N 0 Calculated: 60.16 5.59 5.01 6.34 Found: 59.71 6.01 5.40 6.00

EXAMPLE 1 1 In 2.5 ml of dimethylformamide was dissolved 213 mg of 6-methylenetetracycline hydrochloride and after adding to the solution 165 mg of N-cyclohexenyl piperidine, the mixture was stirred for 3 hours at room temperature. After the reaction was over, piperidine hydrochloride thus precipitated was filtered off and 7 ml of methanol was added to the filtrate, whereby crystalline N-cyclohexenyl--methylenetetracycline was precipitated. The amount of the product was 183 mg. The product was recovered by filtration and purified by recrystallizing from dimethylformamide-methanol. Nuclear magnetic resonance: Alkene hydrogen 74.0 (1H) (c0 c1.

Elemental analysis as C H N O Calculated: 66.39 5.97 5.53 Found: 65.97 6.21 5.75

EXAMPLE 12 [n ml of dimethylformamide was dissolved 1.0g of tetracycline and after adding to the solution 0.74g of N-cyclohexylidene piperidinium perchlorate, the mixture was stirred for 4 hours at room temperature. Then, 0. 192g of piperidine was added to the solution and mixture was further stirred for 4 hours. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and after adding 15 ml of water to the residue obtained, the product was extracted twice each with 15 ml of chloroform. After washing the extract with water, the extract was concentrated and mixed with ether and petroleum ether, whereby a precipitate was formed. The precipitate was dissolved in chloroform and after washing the solution with 2% aqueous acetic acid solution and water, ether and then petroleum ether were added to the solution, whereby a precipitate was formed. The precipitate was recovered by filtration and dissolved in a small amount of chloroform and after adding ether and petroleum ether to the solution, the product was reprecipitated to provide 0.1g of N-cyclohexenyltetracycline. Nuclear magnetic resonance: Alkene hydrogen 'r 4.0 (11-1) (CD C1 Elemental analysis as C H N O In 7 ml of dimethylformamide was dissolved 1.0g of tetracycline hydrochloride and after adding to the solution 1.0g of N-cyclohexenylmorpholine, the mixture -was stirred for 14 hours at room temperature. After the reaction was over, the solvent was distilled away under a reduced pressure, water was added to the residue obtained, and the solid precipitated was extracted with chloroform. The extract was washed with water, 2% aqueous acetic acid solution, 2% aqueous sodium bicarbonate solution, and then water and then after drying the extract over anhydrous magnesium sulfate, the solvent was distilled away under a reduced pressure. Then, ether and petroleum ether was added to the residue and the crystalline powder thus precipitated was recovered by filtration to provide 0.5g of N-cyclohexenyltetracycline. Nuclear magnetic resonance: Alkene hydrogen r4.0 (1H) (CD C13) EXAMPLE 14 In 10 ml of dimethylformamide was dissolved 1.0g of tetracycline hydrochloride and after adding 1.0g of N- (2-phenylcyclohexenyl)piperidine to the solution, the mixture was stirred for 5 hours at room temperature. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and the residue was mixed with chloroform. The mixture was stirred and after filtering off insoluble matters, the remaining solution was washed with 3% aqueous acetic acid solution and then water and after drying the solution over anhydrous magnesium sulfate, the solvent was distilled away under a reduced pressure. Then, ether-petroleum ether (1 5 in volume ratio) was added to the residue and the crystalline solid thus precipitated was recovered by filtration to provide mg of N-( 2-pheny1cyclohexenyl)-tetracyc1ine.

Elemental analysis as C H O N H O:

c H N Calculated: 66.0l 6.l9 4.53 Found: 65.85 6.24 4.43

EXAMPLE In 48 ml of dimethylformamide was dissolved 4.88g of tetracycline hydrochloride and after adding to the solution 4.35g of N-(3,4-dihydro-2- naphthyl)piperidine, the mixture was stirred for 16 hours at 60C. After the reaction was over, the reaction product liquid was concentrated under a reduced pressure and the residue dissolved in chloroform followed by washing four times with water. When the chloroform layer thus formed was concentrated under a reduced pressure and mixed with ether, a precipitate was formed. The precipitate was recovered by filtration, dissolved in chloroform, and the solution was washed twice with 2% aqueous acetic acid solution and dried over anhydrous magnesium sulfate. Then, the solution was concentrated under a reduced pressure, ether was added to the concentrate, and the precipitate thus formed was recovered by filtration to provide 2.2g of- N-( 3 ,4-dihydro-2-naphthyl )tetracycline.

Elemental analysis as C H N O Calculated: 67.12 5.63 4.89

Found: 66.90 5.9l 5.00

EXAMPLE 16 In 18 ml ofdimethylformamide was dissolved 2g of tetracycline hydrochloride and after adding 1.9! g of 2-piperidino-3-p-tolyl-2-butene, the mixture was stirred for about 6 hours at room temperature. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and when ether and petroleum ether were added to the residue, a precipitate was formed. The precipi-' tate was recovered by filtration, dissolved in chloroform, after washing the solution with 2% aqueous acetic acid solution and then water, the solution was concentrated, and then ether and petroleum ether were added to the solution, whereby a precipitate was formed. The precipitate was recovered by filtration, dissolved in chloroform, and after adding ether and petroleum ether to the solution, the product was reprecipitated to provide 2g of N-( l-methyl-2-p-tolyl-lpropenyl)tetracycline.

Elemental analysis as C H N O C H N Calculated: 67.33 6. l6 4.76 Found: 67.22 6.43 4.95

EXAMPLE 17 In 18 ml of dimethylformamide was dissolved 2g of tetracycline hydrochloride and after adding to the solution 2.03g of 3-methyl-3-p-tolyl-2piperidino-l-butene, the mixture was stirred for about 6 hours at room temperature. Thereafter, by following the same procedure as in Example 16, 2g of N-[ l-( l-methyl-l-ptriethyl)ethenyl]-tetracycline was obtained.

Elemental analysis as C l-I N O Calculated: 67.76 6.36 4.65

Found: 67.69 6.33 4.80

EXAMPLE ,1 8

In 18 ml of dimethylformamide was dissolved 2g of tetracycline hydrochloride and after adding to the solution 1.8g of l-(2-furyl)-2-morpholino-l-propene, the mixture was stirred for about 6 hours at room temperature. Thereafter, by following the same procedure as in Example 16, 0.2g of N-[ l-methyl-2-(2-furyl)-ethenyl]- tetracycline was obtained.

Elemental analysis as C l-I N O Calculated: 63.27 5.49 5.09

Found: 63.55 g 5.75 4.91

EXAMPLE 19 In 7 ml of dimethylformamide were dissolved lg of tetracycline hydrochloride and lg of N-(6-ethyl-3,4- dihydro-2-naphthyl)piperidine and the solution was heated for 5 hours at C. After the reaction was over, the solvent'was distilled away from the reaction product liquid under a reduced pressure and after adding 5 ml of water to the residue, the product was extracted with chloroform. The extract was washed with 2% aqueous acetic acid solution and then 2% aqueous sodium bicarbonate solution and after drying over anhydrous magnesium sulfate, the solvent was distilled away from the extract. Then, 10 ml of ether was addedto the residue, the powder precipitated was recovered by filtration, and reprecipitated from chloroform-ether to provide 0.6g of N-(6-ethyl-3,4-dihydro-2-naphthyl)tetracycline having a melting point of 172 176C.

Elemental analysis as C H N O C H N Calculated: 67.99 6.04 4.66

Found: 67.86 5.87 4.78

EXAMPLE 20 In 38 ml of dimethylformamide was dissolved 3.80g of tetracycline hydrochloride and after adding to the solution 3.l7g of N-(2-indenyl)piperidine, the mixture was stirred for 16 hours at 50 60C. After the reaction was over, the reaction product liquid was concentrated under a reduced pressure, dissolved in chloroform, and washed thrice with water. lnsoluble'matters precipitated were filtered off. The chloroform layer was then concentrated under a reduced pressure and ether-n hexane l 10 in volume ratio) solvent mixture was added to the concentrate, whereby a precipitate was formed. The precipitate was recovered by'filtration, dissolved in a small amount of chloroform, and ether was added to the solution, whereby a precipitate was formed. The precipitate was recovered by filtration, dissolved in chloroform, and the solution was washed with 2% aqueous acetic acid solution and then water. After drying the solution over anhydrous magnesium sulfate, the solution was concentrated under a reduced pressure and an ether-n-hexane (l 10 in volume ratio) solvent mixture was added to the concentrate to form a precipitate, which was recovered by filtration to provide 0.3g of N-(2-indenyl)-tetracycline.

'Elemental analysis as C H N O C H N Calculated: 66.65 5.41 5.02 Found: 66.38 5.66 5.l6

EXAMPLE 21 In 7 ml of dimethylformamide was dissolved 0.8g of 5-oxytetracycline and after adding to the solution 0.9g

of 3-methyl-2-piperidino-3-p-tolyl-l-butene and further 0.27 ml of 6.5 N aqueous hydrogenchloride in dimethylformamide, the mixture was stirred for 4 hours at room temperature. After the reaction was over, the reaction product liquid was concentrated under a reduced pressure and after adding ml of water, the product was extracted twice each with 30 ml of chloroform. The extract was washed with water, 2% acetic acid solution, and then water and after drying over anhydrous magnesium sulfate, the solvent was distilled away from the extract under a reduced pressure. Then, ether and petroleum ether were added to the residue and the crystalline powder thus formed was recovered by filtration. The product was reprecipitated from chloroform to provide 0.4g of N-[ 1-( l-methyl-l-ptolylethyl )ethenyl]-5-oxytetracycline. Elemental analysis as C H N O C 77 H (71) N (71 Calculated: 66.01 6.19 4.53 Found: 65.89 6.35 4.70

EXAMPLE 22 Calculated: 63.61 5.66 4.50 5.69

Found: 63.30 5.74 4.57 5.60

EXAMPLE 23 In 13 ml of dimethylformamide was dissolved 1.2g of 7-chlorotetracycline hydrochloride and after adding to the solution I.I4g of 3-methyl-2-piperidino-3-p-tolyllbutene, the mixture was stirred for 6 hours at room temperature. Thereafter, by following the same procedure as in Example I6, 0.5g of N-[l-(l-methyl-l-ptolylethyl)ethenyl]-7-chlorotetracycline was obtained.

Elemental analysis as C ,,I-I N O Cl:

Calculated: 64.10 5.86 4.40 5.56

Found: 63.94 5.79 4.54 5.52

EXAMPLE 24 In 16 ml of dimethylformamide was dissolved l.65g of 5-oxy-6-deoxy-tetracycline hydrochloride and after adding to the solution l.65g of 3-methyl-2-piperidino- 3-p-tolyl-l-butene, the mixture was stirred for 5 hours at room temperature. Thereafter, by following the same procedure as in Example 16, 0.5g of N-[l-(lmethyl- 1 -p-tolylethyl )ethenyl ]-5-oxy-6-deoxytetracycline was obtained.

Elemental analysis as C I-I N O C H N (70) Calculated: 67.76 6.36 4.65 Found: 67.50 6.34 4.75

EXAMPLE 25 In 5 ml of dimethylformamide was dissolved 430 mg of tetracycline hydrochloride and after adding to the solution 560 mg of 1-p-methylsulfonylphenyl-2-morpholino-l-propene, the mixture was stirred for 24 hours at room temperature. Thereafter, by following the same procedure as in Example 21, 120 mg of N-( lmethyl-2-p-methylsulfonylphenylethenyl )tetracycline was obtained.

Elemental analysis as C I-I N O S:

C (72) H N 0 Calculated: 60.l8 5.37 4.39 Found: 59.80 5.32 4.04

EXAMPLE 26 In 5 ml of dimethylformamide was dissolved 477 mg of tetracycline hydrochloride and then after adding 338 mg of N-(4,5-dihydro dihydro-3-thienyl)piperidine to the solution, the mixture was stirred for 7 hours at room temperature. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure, water was added to the residue thus obtained, and the crystal formed was recovered by filtration to provide 353 mg of N-(dihydro-3- thienyl)tetracycline.

In addition, the filtrate was extracted with chloroform and the extract was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled away under a reduced pressure, the residue thus obtained was dissolved in acetone, and ether was added to the solution to form a precipitate, which was recovered by filtration to provide 23 mg of N-(4,5-dihydro- 3-thienyl)tetracycline.

Elemental analysis as C I-I O N S:

. c 77 H (%J N 51%) Calculated: 59.08 5.34 5.30 6.07 Found: 6003 5.00 5.33 5.86

EXAMPLE 27 In 20 ml of dimethylformamide was dissolved 2.0g of 6-demethyl-7-chlorotetracycline hydrochloride and after adding to the solution 1.83g of a mixture of 2- piperidino-3-p-tolyl-l-butene and 2-piperidino-3-ptolyI-2-butene, the mixture was stirred for 6 hours at room temperature.

Thereafter, by following the same procedure as in Example 26, 1.0g of the light yellow powder of N-[ ll-p-tolylethyl)ethenyl]-6-demethyl-7- chlorotetracycline was obtained.

Elemental analysis as C H N O Cl:

c 11 N(%) c1 Calculated: 63.10 5.46 4.60 5.82 Found: 62.81 5.33 4.78 6.01

EXAMPLE 28 In 12 ml of dimethylformamide was dissolved 1 .5g of tetracycline hydrochloride and after adding to the solution 2.0g of 2-morpholino-3-(2-thienyl)-2-pentene, the mixture was stirred for 6 hours at room temperature.

After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and after adding water and chloroform to the residue followed by sufficient shaking, the chloroform layer formed was recovered. The extract was washed with 2% aqueous acetic acid solution and then water and after drying over anhydrous magnesium sulfate, the solvent was distilled away under a reduced pressure. When ether and petroleum ether were added to the residue, a precipitate was formed, which was recovered by filtration and dissolved in chloroform. When ether and petroleum ether were added to the solution and the product was reprecipitated, 1.0g of the light yellow powder of N-[ l-methyI-2-(2-thienyl)-l-butenyl]tetracycline was obtained.

Elemental analysis as C I-I N O S:

((7a) H(7) N(7z) W1) Calculated: 62.6l 5.76 4.7! 5.39 Found: 62.75 5.82 4.96 5.52

EXAMPLE 29 In 40 ml of dimethylformamide was dissolved 5.5g of tetracycline hydrochloride and after adding to the solution 6.0g of 3-methyl-2-morpholino-3-(2-thienyl)-lbutene, the mixture was stirred for 7 hours at room temperature. Thereafter, by following the same procedure as in Example 28, 4.0g of the light yellow powder of N-[ l-( l-methyll -(2-thienyl)-ethyl )-ethenyl]tetracycline was obtained.

Elemental analysis as C H N O S:

Calculated: 62.61 5.76 4.71 5.39

Found: 62.69 5.98 4.51 5.48

EXAMPLE 30 In 2.5 ml of dimethylformamide was dissolved 255 mg of tetracycline hydrochloride and after adding to the solution 350 mg of crude l-cyclohexyl-2-morpholino-l-propene, the mixture was stirred for 5 hours at room temperature. After the reaction was over, the reaction product liquid was concentrated under a reduced pressure and after adding a small amount of water to the concentrate, the product was extracted with chloroform. The extract was washed with water, twice with 2% aqueous acetic acid solution, and then thrice with water and after drying over anhydrous magnesium sulfate, the extract was concentrated under a reduced pressure to such an extent that a small amount of chloroform remained. When ether and petroleum ether was added to the concentrate, a precipitate was formed. The precipitate was recovered by filtration, dissolved in a small amount of chloroform, and after adding ether and petroleum ether, the product was reprecipitated, whereby 40 mg of the yellow powder of N-(Z-cyclohexyl-l-methylethenyl)tetracycline was obtained.

Elemental analysis as C H N O C (7:) H N Calculated: 65.71 6.76 4.94 Found: 65.50 6.92 5.11

EXAMPLE 31 In 16 ml of dimethylformamide was dissolved 1.67g of tetracycline hydrochloride and after adding to the solution 1.63 g of a mixture of 3-methyl-2- piperidinoindene and l-methyl-2-piperidinoindene, the mixture was stirred for 17 hours at 40 50C.

Thereafter, by following the same procedure as in Example 30, 120 mg of the yellow powder of N-(3- methyl-2 indenyl)tetracycline was obtained.

Elemental analysis as C H N O Calculated: 67.12 5.63 4.89

Found: 66.90 5.88 5.20

EXAMPLE 32 To 7 ml of dimethylformamide were added 1 g of 1,2- dipiperidino-l-propene and lg of tetracycline hydrochloride under ice-cooling and the mixture was stirred for 2 hours in an ice-water bath. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and after adding 10 ml of water to the residue, the product was extracted thrice each with 5 ml of chloroform. The chloroform extract was then extracted with 2% aqueous acetic acid solution until the aqueous layer became acidic. To the extract was added sodium bicarbonate to adjust the pH thereof to about 7.5 and after washing the extract with 10 ml of ether, the product was extracted thrice each with 10 ml of chloroform. When the chloroform was distilled away from the chloroform extrac t'un 'der a reduced pressure and n-hexane was added to the residue, a powder was precipitated. The powder was recovered by filtration to provide 0.7g of N-(lmethyl-Z-piperidinoethenyl)tetracycline.

Elemental analysis as C H N O,,:

Calculated: 63.48 6.57 7.40 Found: 63.26 6.63 7.23

EXAMPLE 3 3 In 10 ml of dimethylformamide was dissolved 105g of tetracycline hydrochloride and after adding to the solution 1.2g of l(2-quinolyl)2-piperidino-l-propene, the mixture was stirred for 5 hours at room temperature. Afterthe reaction was over, the reaction product liquid was concentrated under a reduced pressure and after adding water to the concentrate, the product was extracted with chloroform. The extract was washed with water, 2% aqueous acetic acid solution, and then water and after drying over anhydrous sodium sulfate, chloroform was distilled away. When ether and petroleum ether were added to the residue, a precipitate was formed. The precipitate was recovered by filtration and dissolved in a small amount of chloroform. Then, ether and petroleum ether were added followed by reprecipitation to provide 0.2g of N l-methyl-2-( 2- quinolyl)ethenyl]tetracycline.

Elemental analysis as C l-l N O C H (70) N Calculated: 66.77 5.44 6.87 Found: 66.33 5.64 7.00

EXAMPLE 34 'propenyl)tetracycline was obtained.

Elementary analysis as C H N O H (70 N (70 Calculated: 63.27 6.29 5.47 Found: 63.36 6.51 6.00

EXAMPLES 35 38 By the same way as above, the following compounds shown by the formula were prepared.

CH CH 5 5 CH 01! N i 11 com-cs0 6 Elemental analysis Number of Example R R6 R alcul ted o nd C(94) 11(5'5) N )5) C(95) (9 "(9 :55 -cu -n --c1 53.55 4.59 4.55 58.32 4.37 4.81

C1 r- 36 4211 -ll 57.00 4.98 4.33 57.68 5.09 4.55

a? -cn -u 65.66 6.18 6.90 65.30 6.32 6.73

38 n :u -s-ca -n 59.7? 5.16 5.16 59.44 6.09 5.46

EXAMPLE 39 following the same procedure as in Example 39, 1.1g

In 10 ml of dimethylformamide was dissolved 1.0g of tetracycline hydrochloride and after adding to the solution 0.7g of N-cyclohexenylpiperidine, the mixture was stirred for5 hours at room temperature. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and when water was added to the residue obtained and then the pH of the solution was adjusted to 5 with l N hydrochloric acid, a precipitate was formed. The precipitate was recovered by filtration, dissolved in chloroform after being washed with water, and reprecipitated from chloroformether to provide 0.6g of N-cyclohexenyltetracycline. Nuclear magnetic resonance: Alkene hydrogen 1' 4.0 (1H) (CD C1 Elemental analysis as C H N O 'H O:

Calculated: 61.98 6.32 5.16

Found: 61.58 6.13 5.19

EXAMPLE 40 0 (a-c-u-O r 3.8 (1H) (CD C13) Elemental analysis as C H N O 'H O:

Calculated: 62.58 6.52 5.03

Found: 62.28 6.38 5.25

EXAMPLE 4] in IQ ml of dimethylformamide was dissolved 1.0g of tetracycline hydrochloride and after adding to the solution 0.8g of N-cyclooctenylpiperidine, the mixture was stirred for 5 hours at room temperature. Thereafter, by

of N-cyclooctenyltetracycline was obtained. Nuclear magnetic resonance: Alkene hydrogen 1- 3.9 (1H) (CD C1 Elemental analysis as C H N O 'I-1 O;

Calculated 63.14 6.71 4.91 Found: 6302 6.58 4.72

EXAMPLE 42 To 5 ml of dimethylformamide were added 558 mg of 2piperidino-l-m-tolyl-l-butene and 625 mg of tetracycline hydrochloride and then the mixture was stirred for 6 hours at room temperature.

After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and the residue obtained was extracted with chloroform. The chloroform extract was washed with 3% aqueous acetic acid solution and then water and after drying over anhydrous magnesium sulfate, the solvent was distilled away under a reduced pressure. The residue obtained was dissolved in a small amount of acetone, petroleum ether was added to the solution, and the precipitate thus formed was recovered by filtration and dried to provide 730 mg of the light yellow powder of N-[ l-ethyl-2-m-tolylethenyl]tetracycline.

Elemental analysis as C H N O C H (7:) N (7:) Calculated: 67.33 6.16 4.76 Found: 67.59 6.33 4.87

EXAMPLES 43 46 lilemcntal analysis Number of Example R .R R Calculated Fou d C(56) i105) M26) c(%) (2.2) N(%) 43 H CI'I -ll 67.33 6.16 4.76 67.61 6.43 4.49

44 -Cll Cll3 -Cll (37.76 6.36 4.65 68.18 (3.71 4.23

45 -Cll CIl -Cll 67.76 6.36 4.65 67.28 (5.08 0

U CH 46 -Cll -Cll Cll3 -ll 63.27 6.29 5.47 63.01 6.53 5.18

EXAMPLE 47 25 provide 453 mg of N-(l-(l-methyl-l-m- To 4 ml of dimethylformamide were added 550 mg of 3-methyl-2-piperidino-3-m-tolyl-l-butene and 490 mg of tetracycline hydrochloride and the mixture was stirred for 5 hours at room temperature. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure. The residue obtained was dissolved in chloroform and the chloroform solution was washed with 3% aqueous acetic acid solution and then water and after drying over anhydrous magnesium sulfate, the solvent was distilled away. The residue was dissolved in ether, and after adding petroleum ether to the solution, the precipitate formed was recovered by filtration and dried to tolylethyl)ethenyl] tetracycline.

Elemental analysis as C H N O EXAMPLES 48 52 By the same way as above, the following examples were prepared.

CH .3 a

Elm u-cat; al nhalysls Number of Example R5 R6 R7 Calculated Found cm) not) met) C(78) n05; M96) as :n Q .cn 60.33 6.31 4.62 04.09 0.52 4.17

cu cn cn '1 CH so f -Cli 67.16 6.36 4.65 67.55 6.21 4.87

EXAMPLE 53 In 40 ml of dimethylformamide was dissolved 4.1g of tetracycline hydrochloride and after adding dropwise 4g of l-(p-chlorophenyl)-2-piperidinopropene to the Solution at room temperature, the mixture was stirred for 5 hours at room temperature. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and the residue was washed with water and dissolved in 200 ml of chloroform. Further, the solution was washed thrice with water and after drying over anhydrous sodium sulfate, chloroform was distilled away. When ether was added to the residue, a solid product was precipitated, which was recovered by filtration, dissolved in 200 ml When ether-petroleum ether (1 3) mixture was added to the residue, 3g of N-(Z-p-chlorophenyl-lmethylethenyl)tetracycline was precipitated.

Elemental analysis as C H N O Cl:

By the same way as above, the following compounds were prepared.

of chloroform, and washed twice with 2% aqueous acid R solution. The solution was further washed thrice with 5 R water and after drying over anhydrous sodium sulfate, 601111.0 6

chloroform was distilled away. 20

Elemental analysis Number of Example R5 R6 R7 Calculated ound c(%) 120;) N05) C(93) 11(5) N(%) 00:: l- 3 5., -bll -11 Goals 63.86 5.85 4.51 63.51 6.12 4.35

57 4:11 -li Q a 67.33 6.16 4.76 67.10 6.17 4.86

59 -Cl! Cll C!l Cl! 411 64.67 6.36 5.20 64.26 6.15 5.55

60 -ClI Cl! CllCll --11 66.01 6.15 4.53 65.99 6.13 4.24

62 -u -O-C1l=CllClI CiI 62.45 5.61 5.20 62.60 5.90 5.10

63 -c11 cu cu cn mom-O 60.31 5.79 6.52 65.18 5.62 6.33

EXAMPLE 65 In 10 ml of dimethylformamide was dissolved 1.0g of tetracycline hydrochloride and after adding l.lg of l,l-diphenyl-2-piperidinopropene to the solution. the

formed was recovered and purified from an etherpetroleum ether mixture: 450 mg of N-( l-methyl-2,2- diphenylethenyl)-tetracycline was obtained.

Elemental analysis as C H N O I mixture was strrred for 7 hours at room temperature. 5 Calculated, g 2% After the reaction was over, the solvent was distilled nd; 699] 5,74 442 away from the reaction product liquid under a reduced pressure and after adding water to the residue, the 1 EXAMPLES 66 5 product was extracted with chloroform. After washing By the same way as above, the following compounds the chloroform layer a few times with water, chlorow prepared form was distilled away, an etherpetroleum ether mixture was added to the residue, the precipitate thus 5 3 ca 0.1 formed was recovered by filtratlon. The preclpltate was 5 N dissolved in chloroform and after washing the solution 1 5 OH R with 2% aqueous acetic acid solution and then water, I l

o.r11-c=6 chloroform was distilled away. When petroleum ether n H" 7 was added to the residue and the precipitate thus 01-! 0 OH O Elemental analysis, percent Calculated Found Numberof Example R5 R1 R1 0 H N o H N 66 -H -CH0 Q 66.42 5.75 5.00 66.63 5.00 4.85

67 CH4 H 64.16 5.56 7.46 63.98 5.77 7.45

68 -OH5 H {3 65.08 5.80 4.74 64.96 5.89 4.81

70 CH3 H @715 64.35 5.40.484. 64.12 5.47 5.00

71 -CH3 -H /CH3 67.76 6.36 4.65 67.48 6.32 4.65

72 OH; H Q 66.30 5.06 4.87 66.63 6.14 5.05

l CH:

73 CH3 H CH5 66.89 5.96 4.87 66.78 6.00 4.01

74 011. CH3 CH3 64.46 6.71 5.18 64.21 6.63 5.32

CHO

75 60 -ll "z'-67.76 6.36 4.65 67.75 6.46 4.71

:s ctr 0 I -H 64.35 5.92 4.84 64.17 6.02 5.00

-Continued "Elemental analysis Number ot' Example R5 R6 R7 Calculated Found 004) um) c as) um) M) s1 c A-cn n 41 00.55 5.74 0.05 00.24 5.05 0.09

CN 3 p 0.1 52 4111 c c.=1 -11 -11 00.17 0.54 4.54 07.92 0.51 4.05 on a5 -c11 -cn cn :u @011 00.17 0.54 4.54 07.90 0.54 4.55

5 -Cll CH Cll Cll Cll @011 0a .77 0 .41 4 .40 05.40 0 .07 4 .72

q.- s v 88 5 z' z s U 05.15 5.90 4.01 05.00 5.00 -:4.00

09 -cu -(c:1 c1! "61] 05 05 0 5 4 so 05 55 0 41 4.50

Cu 90 -H -11 05.15 5.90 4.01 02.94 5.70 4.01

I d 91 "f'@ -11 -11 05.05 0.15 4.50 03.35 0.00 4-7 c1:,,cii,,c1z 1 cn 05 *3 c -ll -H 05.55 0.51 4.02 05.10 0.40 4.71

11 0.1 11 wm" m a 9",, s4 0 -u 41 05.79 0.50 4.51 05.90 0.55 4.75

EXAMPLE 96 In 17 ml of dimethylformamide was dissolved 1.7g of tetracycline hydrochloride and after adding dropwise 1.3g of 4-piperidino-3-heptene to the solution at room temperature, the mixture was stirred for 5 hours at room temperature. After the reaction was over, the solvent was distilled away from the reaction product liquid under a reduced pressure and water was added to the residue, whereby a solid product was precipitated. The precipitate was recovered by filtration to provide 1.8g of N-( l-propyl-l-butenyl)tetracycline. The product was almost pure but the product was dissolved in chloroform, the solution was washed with water, and after drying over anhydrous sodium sulfate, chloroform was distilled away. The residue was dissolved in ether and repreclpitated from n- EXAMPLES 97 143 By the same way as above. the following compounds were preared.

CH CH CH OH ,2, 5

R R I l 6 CORK-04k I OH Ii OH OH Elemental analysis, percent Calculated Found Number of Example R R5 R.- C H N C H N J7 H CH2CH3 -CH2CH3 61.75 6.66 5.14 61.32 6.81 5.60

98 CH3 H 66.42 5.75 5.00 65.96 5.00 5.26

100 H -11 -CH 59.75 6.02 5.57 59.63 6.86 5.41

101 H CH CH 62.64 6.07 5.62 62.52 6.19 5.81

102 f: E H 69.44 5.50 4.50 69.64 5.75 4. 85

104 --OH. H 3 62.57 5.25 4.71 62.51 5.35 4.91

105 C11. CH 01 63.10 5.46 4.60 62.95 5.29 4.85

105 -cll3 -CH,,CII=C1| 0C1, 04.30 5.55 4.41 64.11 5.04 4.75

107 "CH:s -ll Dr 58.22 4.89 4.38 53-01 4.95 1.58

(ill3 103 i-C1 -11 -ll (53.01 5.66 4.50 63.33 5.74 4.76 cu 109 -Cll:5 '0 5-4. 8 5.59 4.86 64.48 5.31 5.05

(3113 111 -Cl! Cll2-l'-Cllz- -ll 60.31 6.33 7.54 59.88 6.33 8.01

112 -CH -(clI C1l 64.97 0.91 5.05 64.81 7.66 5.13

113 -Cll 0 61.47 0.34 4.94 61.56 5.05 5.04

3.- I CH 115 J -Q- cn u -11 -11 68.17 6.54 4.54 66.45 6.69 4.75

116 CH3 CH3 67.76 6.36 4.65 67.77 6.39 4.77

CH2CH3 117 (fHll "H 08.17 6.54: 4.54 08.21 6.73 4. 71

CHzCHa 118 CH5 -H 66.89 5.97 4.87 66.85 6.19 5.18

119 -CH3 CH3 65.55 6.00 4.03 65.30 5.98 4.60

-Cminued Elemental analysis, percent Calculated Found Number of Example R R6 R1 C H N C H 121 CH2CH3 CHa Q 67.33 6.16 4.76 67.07 6.12 5.02

123 -CH2CH3 CH: 67. 76 6. 36 4. 65 67. 28 6. 39 4. 28

124 -CH2CH: CH2CH; @CH 68. 16 6. 54 4.. 54 67. 68 6. 61 4. 71

CH3 -CH3 62. 06 5. 55 48. 2 61. 83 5. 48 4. 71

126 CH3 CH H 2. 06 5. 55 4. 82 61. 74 5. 4'2 4. 51

128 CHzGHzCI-Ig Q 67.00 6.04 4.66 68.10 6.13 4.73

129""....... OH3 CH1OH3 64.35 5.02 4.84 63.84 5.92 4.94

130 CH3 -CH2CH9CH3 Sameasabove. 64.85 6.12 4.73 64.46 6.08 4.82 131.. --CH= -CH3 d0 65.68 5.88 5.11 62.85 5.85 4.65

132 CH1 -CH2CH3 Q 69.58 6.00 4.30 60.22 6.11 4.22

a CH3 Same as above 69.22 5.81 4.48 69.13 5.95 4.30 CH.1 CHzGI-IzCH3 .d0 60.02 6.18 4.20 69.46 6.23 4.39

( 211. -11 -11 69.58 6.00 4.39 60.42 6.13 4. as 6 CH3 Q 136 cn;. -11 Q 68 64 5 61 4. 50 69 1s 5 71 4 45 137 CH3 H H 68.55 6.71 4.44 68.21 6.70 4.46

I T- CII3 133 -CH3 -CH:; 63.86 5.85 4.51 63. 37 5.94 4. 43

S CH;

139 -CH3 CH3 I I 64.35 5. 92 4.84 63.93 5. J4 4.87

CIII! 11 H 64. 85 6. 12 4. 78 64. 62 6. U7 4. 76

Cl c111 -(ontinucd Elemental analysis, percent Calculated Found Number of Example R Re R: C H N C H N 141 .-CH:; CH2CH2CH:; W 65.33 6.31 4.62 64.92 6.22 4.38

O Cl-ls 142 0H=. CH3 T 68.1? 6.54 4.54 67.94 0.51, 4.01 H l V 0 CH3 0m 143 -CH2CH9CH&CH2 CO 65.01 5.01 4.33 64.73 5.7!! 4.61

Elemental Analysis:

C ('70 H(%) N07!) Calculated 60.42 5.80 5.03 Found 60.10 6.10 5.22

EXAMPLE 146 Elemental Analysis:

1. An N-alkenyltetracycline derivative represented by the formula R R R CONH"CFC wherein R represents a hydrogen atom or a halogen atom; R represents a hydrogen atom or a methyl group; R represents a hydrogen atom or a hydroxyl group; R represents an alkyl group or a thienyl alkyl group; R represents a hydrogen atom, a thienyl group or a methyl thienyl group or said R and R when combined with each other form a l-thiapropylene group or Z-thiabutylene group; R represents a hydrogen atom or an alkyl group; with the proviso that at least one group of R R and combination group of R and R is a group including sulfur atom.

2. A compound according to claim 1 which is N-[ methyl-2-( 2-thienyl l -butenyl ]-tetracycline.

3. A compound according to claim 1 in which R, and R, are hydrogen atoms, R is a methyl group, R is a hydroxyl group, R is an alkyl group or a thienylalkyl group, R is a hydrogen atom or a thienyl group and R-, is a hydrogen atom or an alkyl group.

4. A compound according to claim 1 which is N- l- [2-(2-thienyl)-propyl]ethenyl tetracycline.

5. A compound according to claim 1 which is N-[ methyl-2-(2-thienyl)- l-hexenyl1tetracycline.

6. A compound according to claim 1 which is N- l- [2-( 2-thienyl)-2butyl]ethenyl tetracycline.

7. A compound according to claim 1 which is N- l- [2-( Z-thienyl)-2-pentyl]ethenyl tetracycline. 

1. AN N-ALKENYLTETRACYCLINE DERIVATIVE REPRESENTED BY THE FORMULA
 2. A compound according to claim 1 which is N-(1-methyl-2-(2-thienyl)-1-butenyl)-tetracycline.
 3. A compound according to claim 1 in which R1 and R4 are hydrogen atoms, R2 is a methyl group, R3 is a hydroxyl group, R5 is an alkyl group or a thienylalkyl group, R6 is a hydrogen atom or a thienyl group and R7 is a hydrogen atom or an alkyl group.
 4. A compound according to claim 1 which is N-( 1-(2-(2-thienyl)-propyl)ethenyl)tetracycline.
 5. A compound according to claim 1 which is N-(1-methyl-2-(2-thienyl)-1-hexenyl)tetracycline.
 6. A compound according to claim 1 which is N-(1-(2-(2-thienyl)-2-butyl)ethenyl)tetracycline.
 7. A compound according to claim 1 which is N-(1-(2-(2-thienyl)-2-pentyl)ethenyl)tetracycline. 